项目名称： 纺锤体组装检验点在细胞有丝分裂中作用机制的系统研究

项目编号： No.31671412

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 生物科学

项目作者： Jungseog Kang

作者单位： 上海纽约大学

项目金额： 25万元

中文摘要： 在真核细胞有丝分裂过程中，染色体分离的准确性对维持遗传稳定性具有重要作用。染色体分离异常会导致细胞出现异倍体，从而引发流产，新生儿先天缺陷和癌症。纺锤体组装检验点对染色体分离调控至关重要，它可以检测微管是否正确地附着到染色体上。目前就纺锤体组装检验点功能机制的研究有很多，但仍存在一些未知环节，以至于人们对细胞遗传稳定性的调节机制达不到完整的认识。. 在纺锤体组装检验点激酶中，我们将聚焦在Mps1。当微管错误地附着在染色体上时，Mps1将启动检验点信号。另外，Mps1在染色体排列和DNA损伤修复中也具有重要作用，从而保证遗传稳定性。为寻求分子之间的联系，我们研究发现，Mps1有两个相互作用的分子，一个是着丝粒组蛋白H2A的突变体H2A.Z，另一个是在DNA损伤通路中的癌蛋白MCRS1。我们在Mps1与H2A.Z和MCRS1分子间相互作用研究中提出假设，H2A.Z和MCRS1的下调会引起细胞遗传的不稳定性。我们还将对着丝粒组蛋白翻译后修饰及其异倍体的相关性进行计算分析。这些研究，通过提供分子机制线索，使细胞在异倍体情况下得以存活，这为治疗癌症提供正确的治疗靶点具有重要意义。

中文关键词： 细胞周期检验点；蛋白激酶；组蛋白修饰；基因组不稳定；肿瘤发生

英文摘要： Accurate chromosome segregation in mitosis is essential for keeping genetic stability of eukaryotic cells. Any defect in this process results in aneuploidy, a common cause of miscarriage and birth defect as well as a hallmark of cancer (Hanahan and Weinberg, 2011). The conserved mitotic machinery precisely orchestrates chromosome segregation to keep genetic stability of eukaryotic cells. The spindle assembly checkpoint plays a key role in this process by monitoring correct microtubule attachment onto chromosomes. Although much progress has been made in the study of functional mechanism of the spindle assembly checkpoint, many links are still missing to understand its complete picture in regulating genetic stability of cells. .Among the spindle assembly checkpoint kinases, we will focus on Mps1. Mps1 plays a critical role in initiating checkpoint signaling upon incorrect microtubule attachment but it also play additional roles in chromosome alignment or DNA damage repair to keep genetic stability. In our current studies to seek its molecular links in these processes, we have found that H2A.Z, a centromeric histone H2A variant, and oncoprotein MCRS1 that functions in the DNA damage pathway, are its interacting partners. We here propose to study the molecular interaction of Mps1 with H2A.Z and MCRS1 and the genetic instability caused by deregulation of H2A.Z and MCRS1 in many cancers. We will also perform in silico analysis of post-translational modifications of centromeric histones and their correlation with aneuploidy. These studies will shed light on the molecular mechanism that cancer utilizes to survive under aneuploidy and provide therapeutic targets or strategies for cancer treatment.

英文关键词： Cell cycle checkpoint;Protein kinases;Histone modification;Genome instability;Tumorigenesis